Regulation of interleukin 1 signalling through integrin binding and actin reorganization: disparate effects on NF-kappaB and stress kinase pathways.
Interleukin 1 (IL-1)-mediated gene regulation is dependent on cell-matrix interactions. Both IL-1-activated pathways, nuclear factor kappaB (NF-kappaB) and the stress-activated protein kinase (SAPK), can be regulated by cell adhesion and changes in the cytoskeleton, suggesting that cell-matrix effects on IL-1 responses are initiated in part though effects on signal transduction. Here we show that IL-1-induced transient alterations in cell shape and in the cytoskeleton in fibronectin attached cells are correlated with effects on peak activity of NF-kappaB and SAPK. Cells on fibronectin showed a 1.5-2-fold enhancement in IL-1-induced NF-kappaB activity compared with levels in cells on poly(l-lysine) or bare tissue culture plates. The effect was increased with increasing concentrations of fibronectin and was most prominent at lower concentrations of IL-1. In contrast, fibronectin attachment caused an approx. 50% decrease in the IL-1 activation of SAPK, eliminating the peak activity after 15 min of stimulation with IL-1. IL-1-induced NF-kappaB activity showed a successive, substratum-independent increase during 4 h of attachment and spreading, whereas the inhibitory effect of fibronectin on the SAPK pathway was induced at the initial stages of attachment. Further, the addition of a peptide containing the motif RGD resulted in a 40% decrease in NF-kappaB activity in cells on fibronectin, largely accounted for by an effect on the p50/p65 heterodimer. Similarly, blocking of integrin aggregation by RGD-containing peptide resulted in a total abrogation of the fibronectin effect on IL-1-induced SAPK activity. The results demonstrate disparate effects of cell adhesion on the activation by IL-1 of the NF-kappaB and SAPK pathways. Thus fibronectin attachment causes an up-regulation of NF-kappaB activity in the presence of IL-1, whereas in contrast it results in a pronounced decrease in IL-1-induced SAPK activity.
Zhu
P
P
Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.
Xiong
W
W
Rodgers
G
G
Qwarnstrom
E E
EE
D000199:Actins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002448:Cell Adhesion; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D007375:Interleukin-1 / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D009842:Oligopeptides / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D000199:Actins; D005353:Fibronectins; D016023:Integrins; D007375:Interleukin-1; D016328:NF-kappa B; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D006493:Heparin; D017871:Calcium-Calmodulin-Dependent Protein Kinases